Staving Off Type 1 Diabetes with Immune Therapy

Researchers at UCSF are finding success in altering the natural, and previously inexorable, course of type 1 diabetes. Through various drugs, including antibody therapies, the researchers hope to save or preserve the function of insulin-producing beta cells in the pancreas. "What we are doing is modulating immune function, so that the body doesn't attack the pancreas's beta cells," says Stephen Gitelman, MD, professor of clinical pediatrics and director of the Pediatric Diabetes Program. Type 1 diabetes is an autoimmune disorder in which the body's T cells attack insulin-producing beta cells in the pancreas. The disorder used to be called juvenile-onset diabetes, but it is now known to afflict people at any age. "We are realizing now that over half the new cases are in people over 18 years of age," Gitelman says. "An additional concern is that the incidence of type 1 diabetes is increasing at about 3 percent per year, particularly in those under age 5." Although type 1 diabetes results when the immune system attacks the body's own tissues, using targeted antibodies may prove to be the best therapy. Jeffrey Bluestone, PhD, director of the UCSF Diabetes Center, has developed a monoclonal antibody that latches onto the CD3 receptor on the T cell. When the antibody is introduced, T-cell counts drop as the monoclonal antibody attacks the cells that have the CD3 antibodies attached. When the T-cell population recovers several weeks after the initial drop, the new T cells don't seem to attack the body's insulin-producing cells in the same way. "We are resetting the immunological Œrheostat,'" Gitelman says. "Because patients don't seem to require ongoing therapy, we appear to be inducing immunomodulation, rather than immunosuppression." Gitelman and colleagues' studies indicate that a two-week treatment with the antibodies, when initiated within two months of initial diagnosis, can prolong the "honeymoon" phase of diabetes, when endogenous insulin secretion still occurs. Even after a diagnosis of diabetes, he says, a patient typically still has at least 10 percent to 20 percent beta cell function during the honeymoon phase. Gitelman has found that with antibody therapy, this residual beta cell function can remain for more than 12 months. The effect starts to wane after that time for most treated patients, although at two years most still retain significantly more insulin production than those who did not receive such treatment. "It's extremely important to conserve the endogenous insulin secretion that you still have during the honeymoon phase," Gitelman says. "Even when patients have to take insulin shots, if they can continue to make some of their own insulin, it's much better for long-term outcomes. Those patients who continue to make their own insulin for longer periods of time have better blood sugar control, lower risk of hypoglycemia and lower risk for long-term complications. "It's like the difference between riding a bike versus riding with training wheels. It's very hard to fall over and do something wrong when some of your beta cells are functional." New Studies The initial finding has spawned a series of new studies and clinical trials. Gitelman and his colleagues are investigating how altering the timing of the antibody treatments or supplementing them with other drugs can affect outcome. With the anti-CD3 monoclonal antibody, they are trying to see whether they can improve on the results in the initial study by offering an additional course of treatment 12 months after the first treatment. The researchers are now trying to find the window of treatment effectiveness, and will soon begin a trial to give the antibody to people four to 12 months after their initial diagnosis. They are also planning studies to see whether combining anti-CD3 therapy with drugs that work by different mechanisms may result in synergistic responses. One study in the planning stages utilizes exenatide (Byetta), which has been shown to help preserve beta cell function in animal models of type 1 diabetes. In addition, Gitelman and colleagues are exploring other immuno- modulatory agents against new-onset type 1 diabetes to evaluate their efficacy and safety, and to compare them with the effects of anti-CD3 therapy. One study uses mycophenolate mofetil (CellCept), with or without an IL-2 receptor blocker. Another study uses the anti-CD20 rituximab (Rituxan) to determine whether B cells play a role in type 1 diabetes. Gitelman and his colleagues are currently taking new patients for clinical trials. People with type 1 diabetes who are ages 8 to 45 and have been newly diagnosed during the last six weeks to 12 months are eligible to enroll in the new-onset intervention studies. Ultimately, Gitelman and other researchers hope to head off diabetes before it strikes. "We have a pretty good crystal ball, and we can predict who is going to get diabetes by looking for antibodies against beta cells, doing a genetic screen and doing a metabolic test like the oral glucose tolerance test," he says. "We are currently developing a clinical trial to block progression to diabetes in those who are found to be at risk. "We know how to manage diabetes on a certain level, but the technology we have is imperfect," Gitelman says. "There really is no substitute for the beta cells themselves, so we want to do everything we can to preserve them." For more information, contact Dr. Gitelman at 415/476-3748. Related Links: UCSF Diabetes Center Clinical Trial Volunteer Information